Association Between the Use of 4 Recommended Drug Categories and Patient Perceptions of Health Status Following an ACS Event

BACKGROUND: Four categories of medication have been shown to reduce mortality following an acute coronary syndrome (ACS) event: (a) antiplatelets, (b) beta-blockers, (c) statins, and (d) angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). OBJECTIVES: To determine the association between use of 1 or more of 4 categories of evidence-based medications and patient-perceived health status. METHODS: Data from the registry of a large university-based health system were used for an analysis of prescribing at discharge following an inpatient hospitalization for ACS. Use of evidence-based medications and patient perceived health status were measured in a telephone survey administered 6 to 12 months (mean [SD]=10 [3.5] months) after hospital discharge. Surveys were conducted from January 2002 through March 2005. Subjects were included in the survey if they were prescribed at least 1 of the 4 evidence-based drug categories at the time of discharge. Each patient was assigned to 1 of 5 groups (range: 0 to 4) based on the number of drug categories self-reported by the patient as current at the time of the survey. Patient-perceived health status was assessed using the question “How would you rate your health at the present time?” using a 5-point scale from excellent (1) to poor (5). Mean perceived health status scores for each of the 4 evidence-based medication categories were compared using Analysis of Variance (ANOVA). Multivariate logistic regression determined the association between patient-perceived health status—dichotomized to excellent/ very good/good versus fair/poor—and the evidence-based medication group, controlling for patient demographics and comorbidities. P values of less than 0.05 were considered statistically significant. RESULTS: A total of 393 of 1,206 patients (32.6%) responded to the survey between 6 and 12 months after discharge for an ACS event. The mean (SD) patient-perceived health status ranged from 3.3 (1.1) for patients with no (0) self-reported evidence-based medications (n=14) to 2.5 (1.0) for patients with 4 evidence-based medications (n=130, P=0.028), indicating higher self-perceived health status for patients who were taking more of the evidence-based medications. Using patients with no (0) evidence based medications as the comparator, the odds of higher patient-perceived health status were multiplied by 8.2 (95% confidence interval [CI]=1.7- 37.9, P=0.007) for those with 4 medications, 9.3 (95% CI=2.0-43.4, P=0.004) for those with 3 medications, 4.9 (95% CI=1.1-22.6, P=0.041) for those with 2 medications, and not significantly different for those with 1 medication (odds ratio=2.5, 95% CI=0.4-14.4, P=0.316). Younger age, prior myocardial infarction, and recurrent ACS events occurring between discharge and the survey date were significantly associated with poorer perceived health status. CONCLUSIONS: Better patient-perceived health status was associated with use of a greater number of evidence-based medications for patients with ACS.

• Individually, statins, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and antiplatelet medications reduce mortality and recurrent events in patients who have previously experienced an acute coronary syndrome (ACS) event. • These agents, when used collectively, also reduce morbidity and mortality of cardiovascular-related disease. What is already known about this subject • Self-reported use of 1 or more of these 4 evidence-based medication categories at 6 to 12 months following hospital discharge for an ACS event was associated with better self-reported health status. • Mean (SD) patient-perceived health status score ranged from 3. 3 (1.1) for patients with no (0) evidence-based medications to 2.5 (1.0) for patients with 4 evidence-based medications (P=0.028). • Using patients with no (0) evidence-based medications as the comparator, the odds of higher patient-perceived health status were multiplied by 8.2 (P = 0.007) for those with 4 medications, 9.3 (P = 0.004) for those with 3 medications, and 4.9 (P = 0.041) for those with 2 medications. There was no significant difference in health status score between patients taking 1 versus no (0) evidence-based medication (OR = 2.5, P = 0.316). • Younger age, prior myocardial infarction, and recurrent ACS events were significantly associated with poorer perceived health status.
survey. The list of medications used for this study was developed based on the clinical guidelines and report on quality initiatives by the American Heart Association and the American College of Cardiology. 28,29 In the present study, the combination of agents from each of these 4 drug groups (statins, aspirin, beta blockers, and ACE inhibitor/ARBs) will be referred to as evidence-based therapies. At the time that data collection for the study began (2001), aspirin was the primary recommended antiplatelet agent; other antiplatelet agents, such as clopidogrel, were considered appropriate therapy for patients with coronary or other vascular disease in whom aspirin was contraindicated. 28 Therefore, we chose aspirin as the only antiplatelet for the research described in this report. Patient-perceived health status was measured using the question "How would you rate your health at the present time? In general, would you say your health is excellent, very good, good, fair, or poor?" The responses range from excellent (1) to poor (5). The single-item assessment of patient-perceived health status was chosen for several reasons including (a) its brevity (i.e., using a single item reduces respondent burden and yet still obtains a valid assessment of global perceived health status); and (b) this question has been shown to be a valid predictor of mortality, morbidity, and future health care resource utilization as well as a valid and sensitive measure of patient-perceived health status. [40][41][42][43][44][45][46] ■■ Methods

Registry Patients
This study used retrospective data obtained from the University of Michigan Acute Coronary Syndrome registry. Enrollment of patients in this registry started in 1999 and continues to the present. The registry was developed to assess the quality of care and outcomes of patients admitted to the University of Michigan Health System (UMHS) for an ACS event. The registry includes all patients admitted to UMHS with the diagnosis of ACS. Diagnosis of ACS is based upon symptom history, clinical presentation, electrocardiogram ST-segment changes, and enzyme elevation. Registry data are prospectively collected in 2 phases.
The first phase of data collection involves review of patient medical records by cardiology fellows. The fellow obtains data from the index event (the hospitalization that is used to include the patient in the registry). Collected data include demographics, past medical history, clinical characteristics, inpatient treatment, medications prescribed at discharge (including recommended over-the-counter drugs, such as aspirin), and in-hospital outcomes.
The second phase of data collection for the registry is a telephone follow-up survey of patients, conducted by trained interviewers approximately 6 to 12 months after discharge. The purpose of this survey is to document the occurrence of secondary cardiovascular events, hospitalizations, and cardiovascular procedures and to assess current medication use and health status. patients who experienced a myocardial infarction had alterations in their life goals that were associated with impairment of healthrelated quality of life (HRQL) and onset of depression. 3 Studies of patients with myocardial infarction have measured the effect of illness and interventions on HRQL. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Many of these studies are conducted in the context of controlled clinical trials assessing the effectiveness of an intervention. In health services research, in which the focus of measurement is typically the process of care, ongoing measurement of patient-reported health status provides a way to move from measuring process outcomes to improving care for groups and individual patients.
The relationship between perception of symptoms, alterations in functioning, and global health status was proposed by Wilson and Cleary (1995). 24 In their model, the presence of symptoms impedes an individual's ability to function in a particular domain or domains, which then impacts the patient's perception of global health status. Patient-perceived health status is measured using multiple methods, often depending on the intention of the investigator. Global measures of health status are intended to incorporate a wide range of patient health-references, deriving a general assessment from the physical and mental aspects of health into a single metric. These measures can serve as an indicator of burden of illness, effectiveness of interventions, and projected long-term mortality of patients. 25,26 Patient-perceived health status can be assessed using instruments that produce multiple-scale scores or simple global assessments using a multi-item scale or a single question. Single-item measures are simple to administer, provide a valid and reliable global assessment of health status, and pose minimal respondent burden. 27 The recommended outpatient medication therapy for patients who previously experienced an ACS event includes the concurrent use of lipid-lowering agents, antiplatelet drugs, betablockers, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). [28][29][30] Research has demonstrated a strong association between the collective use of these medications and reductions in the recurrence of cardiovascular events, related hospitalizations, and mortality. One study found that patients prescribed most or all of these medications at the time of discharge had lower risk of mortality and recurrent cardiovascular events after discharge. 31 Other studies provide similar evidence based on appropriate prescribing at discharge or adherent medication taking behavior after discharge. [32][33][34][35][36][37][38][39] The association of the collective use of ACE inhibitors/ARBs, beta-blockers, lipid-lowering therapy, and antiplatelet agents with patient-perceived health status has not been reported. The purpose of this study was to examine the association of the combination of these 4 drug categories and patient-perceived health status using a simple single-item patient-perceived health status measure in patients with a recent history of ACS. It was hypothesized that better perceived health status would be associated with utilization of a greater number of study medications at the time of the the sum of all chronic medications mentioned by the patient during the survey. This variable may serve as a surrogate for overall disease burden. 47 The evidence-based therapy score was the sum of the number of medication categories that patients indicated they were taking at the time of the survey, with a range from 0, meaning no medications, to 4, meaning that the patient reported currently using drugs from all 4 therapeutic categories. A score of 1 for See Appendix A for the medication use and health status portion of the registry survey. At least 5 attempts at different times of the day are made to contact patients. The length of time in days from the date of discharge to the date of telephone contact (interim period time) is recorded as number of months post-discharge for analysis. Variation in interim period time is attributable to a number of factors, including availability of the patient, variations in staffing hours available to conduct telephone calls, and delays in obtaining informed consent from potential subjects. The registry is approved by the institutional review board (IRB) and human investigations committee of the University of Michigan Medical School.
Registry patients used for the present study must have been aged 18 years or older when admitted for treatment of ACS. Measurement of health status with the single-item measure used for the present study began in January 2002 and continued through March 2005. Therefore, the present study is based on registry patients who provided complete data during this time period. In addition, only patients discharged on at least 1 medication from 1 or more of the 4 evidence-based therapy classes-ACE inhibitor/ARB, statin, beta-blocker, and/or aspirin-were included in the study. Table 1 provides a summary of the data used for this study. Independent variables obtained from the registry for this study included demographic variables, comorbidities, cardiovascular events, and an evidence-based medication score. Demographic variables included age, gender, education, and race. Cardiovascular-related comorbidities included diabetes, hyperlipidemia, hypertension, and prior history of myocardial infarction, transient ischemic attack, congestive heart failure, peripheral vascular disease, history of smoking, and atrial fibrillation. Previous history of coronary artery bypass grafting (CABG) surgery and/ or percutaneous coronary intervention (PCI) was recorded. Evidence-based medications prescribed at discharge, including aspirin, beta-blockers, ACE inhibitors/ARBs, and statins, were also abstracted from the registry. ACE inhibitors and ARBs were grouped as a single variable because they are both used in the treatment of hypertension and congestive heart failure, and ARBs are generally given to patients intolerant of an ACE inhibitor.

Data
Cardiovascular events and procedures that occurred between the time of discharge and the telephone survey (interim period) were abstracted from the registry. This information included the occurrence of rehospitalizations for cardiac problems, occurrence of stroke, scheduled or unscheduled coronary revascularization procedures, scheduled or unscheduled cardiac catheterization, or exercise stress tests. A categorical variable termed "exposure" defined whether a patient was readmitted for a cardiac catheterization, PCI, stress test, or CABG during the interim follow-up period. The variable "total number of medications" was derived as you say your health is excellent, very good, good, fair, or poor?" (Appendix) This measurement was assessed using a 5-point Likert scale ranging from excellent (1) to poor (5).

Analysis
Calculations included means and standard deviations for continuous variables and frequencies and percentages for categorical variables. The statistical significance of between-group differences in the median patient-perceived health status scores, comparing patients in each of the 5 medication categories, was assessed using the Kruskal-Wallis test. Post-hoc pair-wise analyses of the differences between the mean patient-perceived health status scores of patients in each of the medication categories were performed using Analysis of Variance (ANOVA) with Scheffé tests. The degree of association between evidence-based medication scores and patient-perceived health status, controlling for age, gender, education, presence or absence of each cardiovascularrelated comorbid condition, sum of all medications (representing overall burden of illness), interim time duration, and cardiovascular interventions or events, was determined using multivariate logistic regression. Patient-perceived health status scores were dichotomized to excellent, very good, or good versus fair or poor. Nonsignificant independent variables were removed from the model using backward stepwise elimination until only the evidence-based medication score categories along with other independent variables with a P value of < 0.05 remained. The model c-statistic and Hosmer-Lemeshow test chi-square were calculated to assess the strength of the model. SPSS version 11.5 was used for analysis (SPSS Inc., Chicago, IL), and the criterion for statistical significance was P < 0.05.

■■ Results
A total of 1,506 patients were admitted to the hospital for ACS during the study period ( Figure 1). Of these, 39 expired during hospitalization, leaving 1,467 patients who were discharged and prescribed at least 1 of the 4 evidence-based medication categories. Of these, 145 had documented contraindications for use of at least 1 study drug and were therefore excluded. An additional 63 died during the interim period between discharge and telephone follow-up survey, leaving 1,259 patients who were eligible to be contacted during the follow-up period. Of these, 53 were unable to be located, leaving 1,206 potential survey patients. Of these, 718 did not provide consent. Of the remaining 488 who were contacted and provided consent to participate, 95 were excluded because they provided incomplete data. The result was a sample of 393 (32.6% response rate) patients who were used for this analysis. No significant differences were observed between respondents (n = 393) and nonrespondents (n = 718) with respect to age, gender, race, or previous history of cardiovascular illness. The mean (SD) time between discharge and telephone follow-up was 10 (3.5) months, range of 6 to 12 months. each category was chosen for several reasons. First, no research exists that assesses the relative influence of each of these drug categories on perceived health status. Without prior data on which to base a score assignment, the decision was made to weight all 4 categories equally. Second, research investigating the relationship between collective evidence-based therapies and mortality also used an equally weighted score of 1 assigned to drug categories. 31 The dependent variable in this analysis was patient-perceived health status, which was assessed using the question "How would you rate your health at the present time? In general, would Characteristics of the study sample are provided in Table 2. The mean (SD) age of respondents was 63.7 (12.9) years. The majority of patients were male (64.1%), most were Caucasian (89.1%), and 57.3% had attended college. Nearly one-third (31.8%) experienced at least 1 cardiovascular procedure or event (cardiac catheterization, CABG, or stress test) during the interim period between discharge and telephone follow-up survey. The most commonly documented cardiovascular-related comorbidities or risk factors present at the time of admission for the index event included hypertension, hyperlipidemia, and smoking.
At the time of the telephone survey, approximately one-third (33.1%) of respondents indicated that they were taking all 4 classes of medications; more than one-third (36.4%) indicated taking 3 of the 4 classes of medications; and less than one-third indicated that they were taking 2 or fewer evidence-based medications. The majority of subjects (78.4%) reported their perceived health status to be excellent, very good, or good. Table 3 presents the distribution of mean patient-perceived health status scores by evidence-based medication score. Better patient-perceived health status was associated with self-reported use of more evidence-based medications. The Kruskal-Wallis test statistic was significant (P = 0.044), as was the ANOVA statistic (P = 0.028). However, no paired comparisons of patient-perceived health status by medication score categories were statistically significant using the Scheffé test. Table 4 presents the final multivariate logistic regression model results with dichotomized patient-perceived health status as the dependent variable. The model c-statistic was 0.745, with a Hosmer and Lemeshow chi-square of 6.534 (P = 0.588). Better patient-perceived health status (excellent, very good, or good) was associated with a higher evidence-based medication score. Using patients with no (0) evidence-based medications as the comparator, the odds of higher patient-perceived health status were multiplied by 8.2 (95% confidence interval [CI] = 1.7-37.9, P = 0.007) for those with 4 medications, 9.3 (95% CI = 2.0-43.4, P = 0.004) for those with 3 medications, and 4.9 (95% CI = 1.1-22.6, P = 0.041) for those with 2 medications. The odds ratio (OR) of higher health status for the group taking 1 medication was 2.5 (95% CI = 0.4-14.4, P = 0.316) but was not statistically significant. Therefore, taking 2, 3, or 4 evidence-based medications was significantly associated with higher patient-perceived health status compared with taking no evidence-based medications. Additional significant variables in the model included age, history of myocardial infarction, and experiencing a cardiovascular event or procedure after discharge. History of previously documented myocardial infarction was associated with lower patientperceived health status (OR = 0.3, 95% CI = 0.2 to 0.6, P < 0.001). Additionally, the exposure variable was significant, indicating that patients who experienced a cardiovascular-related procedure or event during the interim period indicated a 50% reduction in the odds of reporting higher perceived health status (OR = 0.5,  Rasmussen et al. (2007) studied the relationship between adherence to cardiovascular medications and the long-term risk of mortality following an ACS event. In their analysis, the authors adjusted for sociodemographic factors, illness severity, and comorbidity using multivariable survival models with propensity analysis. 49 Their findings suggest that the benefits of these agents on long-term mortality are related primarily to the drug effects. The present study did not measure patient engagement in lifestyle modifications or behaviors that might reduce cardiovascular risk or improve health status. Future studies should explore the effects of overall healthy lifestyle modification-including diet, exercise, taking medications, and seeing physicians on a regular basis-on quality of life.

Association Between the Use of 4 Recommended Drug Categories and Patient Perceptions of Health Status Following an ACS Event
The analysis used for this study controlled for various patient and illness variables. The age of patients had a varied relationship with patient-perceived health status. The youngest age group, the comparator group for analysis, had greater odds of reporting lower health status than the other groups except the oldest group. The comparative difference was significant for all but the oldest group. It is known that older patients tend to have lower patient-perceived health status assessments compared with younger patients. 50 However, the youngest patient groups also had lower patient-perceived health status compared with patients aged 65-74 years. This difference may be partially explained by the findings of a recently reported study examining the influence of cardiovascular disease on patients' life goals. 3 Younger patients age was associated with better perceived health status. Relative to patients aged 54 years or younger, odds of a higher perceived health status were multiplied by 3.6 for patients aged 55 to 64 years, by 5.0 for patients aged 65 to 74 years, and were not significantly different for patients aged 75 years or older.
Nonsignificant independent variables not in the final model included gender, race, education, cardiovascular-related comorbidities (except history of myocardial infarction), sum of all medications, and interim time period.

■■ Discussion
In the present study, patients who reported taking from 2 to 4 unique evidence-based medications used for the follow-up treatment of ACS reported better patient-perceived health status than patients taking no evidence-based medications. The specific medication combinations associated with better patient-perceived health status were not assessed in this study due to the relatively small subsample sizes of categories of patients reporting taking specific combinations.
The results of the analysis demonstrate that an association exists between the use of evidence-based medication after an ACS event and patient-perceived health status. This association may be related either to the appropriate prescribing and taking of evidence-based medications after an ACS event or to a phenomenon known as the "healthy adherer effect." Simpson et al. (2006) conducted a meta-analysis of 21 observational studies of interventions to improve medication adherence. 48 The authors found that good adherence to medication therapies was associated with lower mortality, whether patients were taking an active drug or placebo. However, harmful drug therapy was associated with higher mortality rate. The authors hypothesized from their findings that adherence to medications may be a surrogate marker for overall healthy behavior.  delineate the complex relationships between prescribing, disease severity, comorbidity, and perceived health status.

Limitations
First, the study relied on cross-sectional data, and the results can be used only to generate hypotheses for further research. Because of the cross-sectional nature of the data, psychometric properties such as test-retest reliability of the data as well as response shift could not be assessed. Further research including a longitudinal follow-up may provide useful data to support the findings of this study.
Second, the present study did not assess the association of specific combinations of medications or the unique effect of individual medication classes on patient-perceived health status. To do so would have been difficult with the small number of patients receiving specific combinations or only a single medication category out of the 4. A study by Hippisley-Cox and Coupland (2005), which examined the association of various combinations of evidence-based medications and the outcome of mortality after a cardiovascular event, found that beta-blockers, statins, and aspirin in various combinations improved mortality status. 37 Future studies of patient-perceived health status using larger samples should be conducted to examine the conferred benefit of specific combinations of evidence-based medications.
Third, there may have been some patients in the present study who were not using medication because of adverse events or access issues. A 2005 analysis using this dataset showed that the primary reason for discontinuing a medication was that the physician did not feel it was necessary to continue. 51 The current study was designed to determine the outcome of patients on various levels of evidence-based therapy intensity regardless of the reason for not persisting on medication. Future research should continue to determine the relationship between prescriber beliefs and attitudes toward the level of illness of patients and their prescribing behaviors. Such studies may be able to delineate whether inadequate prescribing occurs for sicker patients.
Fourth, the dependent variable used for this study was a single question asking patients to rate their health. Being a general global question, this item may prompt respondents to consider many different aspects of their health when deciding how to answer. It is difficult to determine why an individual chooses a response to a question. The patient may be responding based on physical or mental health-related issues that they perceive as being poorly controlled. They may also be responding to noncardiac-related health concerns. The placement of a question in a survey creates the frame of reference within which the respondent answers the question. The health status question in this survey was placed near the end of the overall survey, following many questions related to medication use and cardiovascular related health.
Fifth, the method used to score the evidence-based therapy, from 0 to 4, using a simple score of 1 for each medication class may have lower perceived health status partly because of frame of reference. Specifically, the development of ischemic heart disease and related events may produce more dissatisfaction, upset, and disappointment in a younger patient than in an older patient who has become accustomed to chronic illness.
Another significant predictor variable, a history of myocardial infarction, may be considered a surrogate for the severity of cardiac disease the patient is experiencing. Need for additional cardiac-related interventions during the interim period between discharge and follow-up (exposure variable in our study) was also associated with more severe cardiac disease. Together these factors were associated with lower odds of favorable patientperceived health status, suggesting that, as expected, recurrent events or the need for further procedures may negatively affect patient perception of well being.
ACS is an umbrella term that includes patients who experience unstable angina, non-ST segment myocardial infarction, and ST-segment myocardial infarction. Each condition is characterized by acute ischemia of the myocardium due to acute blockage of blood flow primarily due to intravascular clot formation. Each condition is associated with a wide variation in the extent of myocardial damage and the permanency of that damage. The influence of the residual effects of acute myocardial ischemic events on patients' functional and health status has been the focus of many research studies over the past several decades. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] These studies have identified many patient, disease, and treatment characteristics associated with health status or HRQOL, including the type of ACS event. The present analysis was not able to control for the type of ACS event because of inconsistent documentation in the ACS registry, the source of data for this project. As well, the type of revascularization procedure performed either during the index event or during the interim period after discharge was not uniformly documented and, therefore, could not be used for analysis.
It may be that patients with better health status were also more likely to be prescribed more evidence-based therapies. For example, patients with better prognosis and functional status might more likely be prescribed a full treatment combination. Likewise, patients with poorer health status may have more severe disease, comorbidities, or medication adverse effects that may lead to the discontinuation of therapy. We did attempt to control for comorbidity using 2 variables, including the total number of medications prescribed for the patient and a list of cardiovascular-related comorbid conditions derived from a predetermined list of conditions documented in the ACS registry. In the regression analysis, we found a positive relationship between comorbidity, as measured by the presence of several cardiovascular comorbid conditions and a greater number of total medications, with lower perceived health status. However, the association was statistically significant for only a single comorbidity variable-previous myocardial infarction. Future research may be able to better the patient was taking at the time of the survey, may not represent an interval scale. No studies to date have documented the relationship between the number of individual drug classes and patient-perceived health status. Future research in this area could assess the relative contribution of each of these drug classes, independently or in various combinations, on patient-reported outcomes such as perceived health status. This study could be considered the first step in identifying a potential relationship worthy of future study.
Sixth, the response rate of 32% was relatively low. However, based on the nonresponse bias assessment, there were no significant differences between respondents (n= 393) and those nonrespondents who met inclusion criteria (n = 718). In particular, age and history of cardiovascular diseases did not significantly differ between the 2 groups.

■■ Conclusion
Among patients who recently experienced an ACS event, selfreported concomitant use of 4 evidence-based medication categories is associated with better patient self-reported health status, compared with use of no evidence-based medications. Further research is needed to delineate the association between specific drug class combinations and perceived health status, as well as to use more refined patient-perceived health status instruments. The potential for the influence of the healthy-adherer effect could also not be ruled out as a contributing factor in the findings.
The results of this study should encourage clinicians to support patient-centered as well as health-system initiatives that promote rational prescribing and medication adherence interventions for patients who recently experienced an ACS event.

DISCLOSURES
Funding was provided by the Mardigian Foundation, Hewlett Fund for Cardiovascular Research in Women, sanofi aventis, and Pfizer, Inc. The funding sources had no involvement in study design, conduct, data collection, analysis, interpretation, review, or revision of this manuscript. All authors indicate they have no conflicts of interest related to the subject of this manuscript.
Study concept and design were primarily the work of Erickson, with the assistance of Eagle. The data were collected primarily by Rangarajan. Smith interpreted the data with the assistance of Erickson. Erickson wrote the manuscript with assistance from Kline-Rogers and Eagle. Erickson made the majority of the revisions with assistance from all coauthors.